Glucose-stimulated Plasma Insulin Levels Research Articles

Cisplatin exposure dysregulates insulin secretion in male and female mice.

Cancer survivors have an increased risk of developing Type 2 diabetes compared to the general population. Patients treated with cisplatin, a common chemotherapeutic agent, are more likely to develop metabolic syndrome and Type 2 diabetes than age- and sex-matched controls. Surprisingly, the impact of cisplatin on pancreatic islets has not been reported. Our study aimed to determine if mouse islet function is adversely affected by systemic (in vivo) or direct (in vitro) exposure to cisplatin. In vivo cisplatin exposure led to deficits in glucose-stimulated plasma insulin levels in both male and female mice, despite no differences in glucose tolerance. In vitro cisplatin exposure to mouse islets dysregulated insulin release and reduced oxygen consumption in a non-sex specific manner. When shifting our focus to male mouse islets, cisplatin altered the expression of genes related to insulin production, oxidative stress, and the Bcl-2 family as early as 6-hours post-exposure. Genome-wide expression analysis confirmed the pronounced downregulation of genes within the insulin secretion pathway in cisplatin-exposed mouse islets. Data from 3 human organ donors confirms that the detrimental effects of cisplatin on insulin secretion and gene expression are reproduced in human islets. Our findings indicate that cisplatin exposure causes significant defects in insulin secretion and may have lasting effects on islet health.

Apigenin potentiates glucose-stimulated insulin secretion through the PKA-MEK kinase signaling pathway independent of K-ATP channels

AimApigenin, a natural bioflavonoid, is reported as an anti-diabetic agent since it possesses the ability to inhibit α-glucosidase activity, cause stimulation of insulin action and secretion, manage ROS, and prevent diabetes complications. Apigenin was identified as a new insulin secretagogue that enhances glucose-stimulated insulin secretion and seems like a better antidiabetic drug candidate. Here we explored the insulinotropic mechanism(s) of apigenin in vitro in mice islets and in vivo in diabetic rats. MethodsSize-matched pancreatic islets were divided into groups and incubated in the presence or absence of apigenin and agonists or antagonists of major insulin signaling pathways. The secreted insulin was measured by ELISA. The intracellular cAMP was estimated by cAMP acetylation assay. The acute and chronic effects of apigenin were evaluated in diabetic rats. Resultsapigenin dose-dependently enhanced insulin secretion in isolated mice islets, and its insulinotropic effect was exerted at high glucose concentrations distinctly different from glibenclamide. Furthermore, apigenin amplified glucose-induced insulin secretion in depolarized and glibenclamide-treated islets. Apigenin showed no effect on intracellular cAMP concentration; however, an additive effect was observed by apigenin in both forskolin and IBMX-induced insulin secretion. Interestingly, H89, a PKA inhibitor, and U0126, a MEK kinase inhibitor, significantly inhibited apigenin-induced insulin secretion; however, no significant effect was observed by using ESI-05, an epac2 inhibitor. Apigenin improved glucose tolerance and increased glucose-stimulated plasma insulin levels in diabetic rats. Apigenin also lowered blood glucose in diabetic rats upon chronic treatment. ConclusionApigenin exerts glucose-stimulated insulin secretion by modulating the PKA-MEK kinase signaling cascade independent of K-ATP channels.

The aryl hydrocarbon receptor in β-cells mediates the effects of TCDD on glucose homeostasis in mice

ObjectiveChronic exposure to persistent organic pollutants (POPs) is associated with increased incidence of type 2 diabetes, hyperglycemia, and poor insulin secretion in humans. Dioxins and dioxin-like compounds are a broad class of POPs that exert cellular toxicity through activation of the aryl hydrocarbon receptor (AhR). We previously showed that a single high-dose injection of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, aka dioxin; 20 μg/kg) in vivo reduced fasted and glucose-stimulated plasma insulin levels for up to 6 weeks in male and female mice. TCDD-exposed male mice were also modestly hypoglycemic and had increased insulin sensitivity, whereas TCDD-exposed females were transiently glucose intolerant. Whether these effects are driven by AhR activation in β-cells requires investigation. MethodsWe exposed female and male β-cell specific Ahr knockout (βAhrKO) mice and littermate Ins1-Cre genotype controls (βAhrWT) to a single high dose of 20 μg/kg TCDD and tracked the mice for 6 weeks. ResultsUnder baseline conditions, deleting AhR from β-cells caused hypoglycemia in female mice, increased insulin secretion ex vivo in female mouse islets, and promoted modest weight gain in male mice. Importantly, high-dose TCDD exposure impaired glucose homeostasis and β-cell function in βAhrWT mice, but these phenotypes were largely abolished in TCDD-exposed βAhrKO mice. ConclusionOur study demonstrates that AhR signaling in β-cells is important for regulating baseline β-cell function in female mice and energy homeostasis in male mice. We also show that β-cell AhR signaling largely mediates the effects of TCDD on glucose homeostasis in both sexes, suggesting that the effects of TCDD on β-cell function and health are driving metabolic phenotypes in peripheral tissues.

Acute Disruption of Leptin Signaling in Vivo Leads to Increased Insulin Levels and Insulin Resistance

Leptin, an adipocyte-derived hormone, plays an essential role in the maintenance of normal body weight and energy expenditure, as well as glucose homeostasis. Indeed, leptin-deficient ob/ob mice are obese with profound hyperinsulinemia, insulin resistance, and often hyperglycemia. Interestingly, low doses of exogenous leptin can reverse the hyperinsulinemia and hyperglycemia in these animals without altering body weight. The hyperinsulinemia in ob/ob mice may result directly from the absence of leptin signaling in pancreatic β-cells and, in turn, contribute to both obesity and insulin resistance. Here, we acutely attenuated endogenous leptin signaling in normal mice with a polyethylene glycol (PEG)ylated mouse leptin antagonist (PEG-MLA) to determine the contribution of leptin signaling in the regulation of glucose homeostasis. PEG-MLA was either injected or continuously administered via osmotic minipumps for several days, and various metabolic parameters were assessed. PEG-MLA-treated mice had increased fasting and glucose-stimulated plasma insulin levels, decreased whole-body insulin sensitivity, elevated hepatic glucose production, and impaired insulin-mediated suppression of hepatic glucose production. Moreover, PEG-MLA treatment resulted in increased food intake and increased respiratory quotient without significantly altering energy expenditure or body composition as assessed by the lean:lipid ratio. Our findings indicate that alterations in insulin sensitivity occur before changes in the lean:lipid ratio and energy expenditure during the acute disruption of endogenous leptin signaling.

Comparison of sub-chronic metabolic effects of stable forms of naturally occurring GIP(1-30) and GIP(1-42) in high fat fed mice

Glucose-dependent insulinotropic polypeptide (GIP) is a 42 amino acid hormone secreted from intestinal K-cells, which exhibits a number of actions including stimulation of insulin release. A truncated form, GIP(1-30), has recently been demonstrated in intestine and islet α-cells. To evaluate the potential physiological significance of this naturally occurring form of GIP, the present study has examined and compared the bioactivity of enzymatically stabilised forms, [D-Ala²]GIP(1-30) and [D-Ala²]GIP(1-42), in high-fat fed mice. Twice-daily injection of GIP peptides for 42 days had no significant effect on food intake or body weight. However, non-fasting glucose levels were significantly lowered, and insulin levels were elevated in both treatment groups compared to saline controls. The glycaemic response to i.p. glucose was correspondingly improved (P < 0.05) in [D-Ala²]GIP(1-30)- and [D-Ala²]GIP(1-42)-treated mice. Furthermore, glucose-stimulated plasma insulin levels were significantly elevated in both treatment groups compared to control mice. Insulin sensitivity was not significantly different between any of the groups. Similarly, plasma lipid profile, O₂ consumption, CO₂ production, respiratory exchange ratio, and energy expenditure were not altered by 42 days twice-daily treatment with [D-Ala²]GIP(1-30) or [D-Ala²]GIP(1-42). In contrast, ambulatory activity was significantly (P < 0.05) elevated during the light phase in both GIP treatment groups compared to saline controls. The results reveal that sustained GIP receptor activation exerts a spectrum of beneficial metabolic effects in high-fat fed mice. However, no differences were discernable between the biological actions of the enzyme-resistant analogues of the naturally occurring forms, GIP(1-30) and GIP(1-42).

Disruption of Hepatic Leptin Signaling Protects Mice From Age- and Diet-Related Glucose Intolerance

OBJECTIVEThe liver plays a critical role in integrating and controlling glucose metabolism. Thus, it is important that the liver receive and react to signals from other tissues regarding the nutrient status of the body. Leptin, which is produced and secreted from adipose tissue, is a hormone that relays information regarding the status of adipose depots to other parts of the body. Leptin has a profound influence on glucose metabolism, so we sought to determine if leptin may exert this effect in part through the liver.RESEARCH DESIGN AND METHODSTo explore this possibility, we created mice that have disrupted hepatic leptin signaling using a Cre-lox approach and then investigated aspects of glucose metabolism in these animals.RESULTSThe loss of hepatic leptin signaling did not alter body weight, body composition, or blood glucose levels in the mild fasting or random-fed state. However, mice with ablated hepatic leptin signaling had increased lipid accumulation in the liver. Further, as male mice aged or were fed a high-fat diet, the loss of hepatic leptin signaling protected the mice from glucose intolerance. Moreover, the mice displayed increased liver insulin sensitivity and a trend toward enhanced glucose-stimulated plasma insulin levels. Consistent with increased insulin sensitivity, mice with ablated hepatic leptin signaling had increased insulin-stimulated phosphorylation of Akt in the liver.CONCLUSIONSThese data reveal that unlike a complete deficiency of leptin action, which results in impaired glucose homeostasis, disruption of leptin action in the liver alone increases hepatic insulin sensitivity and protects against age- and diet-related glucose intolerance. Thus, leptin appears to act as a negative regulator of insulin action in the liver.

Active immunization against (Pro3)GIP improves metabolic status in high‐fat‐fed mice

Ablation of gastric inhibitory polypeptide (GIP) receptor signalling can prevent many of the metabolic abnormalities associated with dietary-induced obesity-diabetes. The present study was designed to assess the ability of active immunization against (Pro(3))GIP to counter metabolic dysfunction associated with diet-induced obesity in high-fat-fed mice. Normal male Swiss NIH mice were injected (s.c.) once every 14 days for 98 days with complexed (Pro(3))GIP peptide, with transfer to a high-fat diet on day 21. Active immunization against (Pro(3))GIP resulted in circulating GIP antibody production and significantly (p < 0.05 p < 0.01) reduced circulating blood glucose concentrations compared to high-fat control mice from day 84 onwards. Glucose levels were not significantly different from lean controls. The glycaemic response to i.p. glucose was correspondingly improved (p < 0.01) in (Pro(3))GIP-immunized mice. Furthermore, circulating and glucose-stimulated plasma insulin levels were significantly (p < 0.01 to p < 0.001) depressed compared to high-fat control mice. Liver triglyceride, pancreatic insulin and circulating LDL-cholesterol levels were also significantly reduced in (Pro(3))GIP-immunized mice. These changes were independent of any effects on food intake or body weight. The glucose-lowering effect of native GIP was annulled in (Pro(3))GIP-immunized mice consistent with the induction of biologically effective GIP-specific neutralizing antibodies. These results suggest that immunoneutralization of GIP represents an effective means of countering the disruption of metabolic processes induced by high-fat feeding.

Long-term effects of vanadyl treatment on streptozocin-induced diabetes in rats.

The vanadate and vanadyl forms of vanadium have been shown by many investigators to have insulinlike effects on glucose metabolism. Many investigators have shown that vanadium, or its salts, counteracts the hyperglycemia associated with streptozocin-induced diabetes (STZ-D) in the rat, although insulin secretion remains depressed. Studies of the action of vanadate on insulin secretion and glucose metabolism have not addressed the question of possible long-term effects of this compound on glucose metabolism extending beyond the period of oral administration. This study was undertaken to assess the effects of treatment (3 wk) and withdrawal of vanadyl sulfate (13 wk) on glucose metabolism, insulin secretion, and islet insulin content of STZ-D rats. Our results indicate that STZ-D rats that have had blood glucose levels normalized by 3 wk of vanadyl treatment remain normoglycemic after 13 wk of withdrawal from treatment. Normal glucose tolerance was observed in vanadyl-treated diabetic animals despite depressed fasting and glucose-stimulated plasma insulin levels. Insulin secretion from the isolated perfused pancreas was greater after vanadyl treatment than in untreated diabetic rats, although it was only 12% of values from controls. Three weeks of vanadyl treatment of STZ-D rats, followed by 13 wk of withdrawal, yielded islets close in size and insulin content of control islets, even though in vivo and in vitro insulin secretion was impaired. This study has shown that short-term vanadyl treatment of STZ-D rats yields normalization of glucose tolerance and protection of islets from destruction by STZ.(ABSTRACT TRUNCATED AT 250 WORDS)

The Impact of Obesity and Chronic Hyperinsulinemia on Gonadotropin Release and Gonadal Steroid Secretion in the Polycystic Ovary Syndrome

We investigated whether obesity was a marker for a neuroendocrinologically distinct form of the polycystic ovary syndrome (PCO). Further, since women with PCO have significantly higher basal and/or glucose-stimulated plasma insulin levels, we also examined the effects of chronic hyperinsulinemia on gonadotropin and gonadal steroid secretion. Ten obese women (nine with acanthosis nigricans) and five nonobese women (one with acanthosis nigricans) with PCO as well as seven obese and six nonobese women of comparable age and weight in the midfollicular phase of their cycles were studied. Pulsatile gonadotropin release was determined for 6-24 h as well as gonadotroph sensitivity to GnRH (10 micrograms, iv). The obese PCO women had significantly increased basal and glucose-stimulated plasma insulin levels compared to the other groups, the nonobese PCO and the obese normal women had similar insulin levels, and the nonobese normal women had the lowest insulin levels. All four groups had similar plasma estradiol levels. Both the obese and the nonobese PCO women had similar and significantly higher mean plasma LH levels, LH pulse amplitude, and integrated LH responses to GnRH compared to values in both normal groups (P less than 0.01 to P less than 0.001); the obese PCO women did not differ from the nonobese PCO women. The mean LH pulse frequencies per 6 h were similar in the four groups. FSH secretion did not differ significantly in the four groups. The levels of the putative gonadal feedback steroids, plasma total and non-sex hormone-binding globulin-bound testosterone, non-sex hormone-binding globulin-bound estradiol, and estrone, were similar in both PCO groups and were significantly higher than those in both normal groups (all P less than 0.001). The only independent effect of obesity was on plasma androstenedione levels and the androstenedione to estrone ratio, both of which were significantly higher in PCO women than normal women (P less than 0.01 to P less than 0.001), but significantly lower in the obese (PCO and normal) women than in nonobese (PCO and normal) women (P less than 0.05). These findings suggest that 1) the impact, if any, of obesity in PCO is not reflected in discernible changes in gonadotropin release or in the gonadal steroid feedback environment; and 2) insulin does not have a major role in the perpetuation of PCO, since obese and nonobese PCO women had similar reproductive hormone levels despite significantly different degrees of hyperinsulinemia.

The impact of obesity and chronic hyperinsulinemia on gonadotropin release and gonadal steroid secretion in the polycystic ovary syndrome.

We investigated whether obesity was a marker for a neuroendocrinologically distinct form of the polycystic ovary syndrome (PCO). Further, since women with PCO have significantly higher basal and/or glucose-stimulated plasma insulin levels, we also examined the effects of chronic hyperinsulinemia on gonadotropin and gonadal steroid secretion. Ten obese women (nine with acanthosis nigricans) and five nonobese women (one with acanthosis nigricans) with PCO as well as seven obese and six nonobese women of comparable age and weight in the midfollicular phase of their cycles were studied. Pulsatile gonadotropin release was determined for 6-24 h as well as gonadotroph sensitivity to GnRH (10 micrograms, iv). The obese PCO women had significantly increased basal and glucose-stimulated plasma insulin levels compared to the other groups, the nonobese PCO and the obese normal women had similar insulin levels, and the nonobese normal women had the lowest insulin levels. All four groups had similar plasma estradiol levels. Both the obese and the nonobese PCO women had similar and significantly higher mean plasma LH levels, LH pulse amplitude, and integrated LH responses to GnRH compared to values in both normal groups (P less than 0.01 to P less than 0.001); the obese PCO women did not differ from the nonobese PCO women. The mean LH pulse frequencies per 6 h were similar in the four groups. FSH secretion did not differ significantly in the four groups. The levels of the putative gonadal feedback steroids, plasma total and non-sex hormone-binding globulin-bound testosterone, non-sex hormone-binding globulin-bound estradiol, and estrone, were similar in both PCO groups and were significantly higher than those in both normal groups (all P less than 0.001). The only independent effect of obesity was on plasma androstenedione levels and the androstenedione to estrone ratio, both of which were significantly higher in PCO women than normal women (P less than 0.01 to P less than 0.001), but significantly lower in the obese (PCO and normal) women than in nonobese (PCO and normal) women (P less than 0.05). These findings suggest that 1) the impact, if any, of obesity in PCO is not reflected in discernible changes in gonadotropin release or in the gonadal steroid feedback environment; and 2) insulin does not have a major role in the perpetuation of PCO, since obese and nonobese PCO women had similar reproductive hormone levels despite significantly different degrees of hyperinsulinemia.

Effect of exercise training on whole-body insulin sensitivity and responsiveness.

Exercise training causes a decline in basal and glucose-stimulated plasma insulin levels and improves glucose tolerance. Furthermore evidence has been presented for effects on both insulin receptors and postreceptor events. However, it is unclear how these changes affect the in vivo dose-response relationship between insulin levels and whole-body glucose utilization. The aim was to examine the effect of exercise training on this relationship and distinguish between changes in insulin sensitivity and responsiveness. Euglycemic clamps were performed in trained (ET, running 1 h/day for 7 wk), sedentary (CON), and sedentary food-restricted ( SFR ) rats. ET rats showed no increase in maximal net glucose utilization in response to insulin (ET 29.5 +/- 0.6 vs. CON 28.2 +/- 1.5 mg X kg-1 X min-1, NS), whereas insulin sensitivity was increased as indicated by the insulin concentration causing half-maximal stimulation (ED50) (49 +/- 20 for ET and 133 +/- 30 mU/l for CON). Thus 7 wk of moderate exercise training resulted in a significant shift of whole-body insulin sensitivity to place ED50 well within the physiological range of insulin concentrations. This would undoubtedly result in improved glucose disposal in the postprandial state and emphasizes the potential benefit of exercise in obesity and type II diabetes.

Effect of physical training on glucose tolerance and on glucose metabolism of skeletal muscle in anaesthetized normal rats

The effect of physical training on glucose tolerance in vivo and skeletal muscle glucose metabolism in vitro was investigated in normal rats. Treadmill running for 10 days up to 240 min/day led to a decrease of basal and glucose-stimulated plasma insulin levels without major alterations of the IV glucose tolerance (1 g/kg body weight). Swim training of two weeks' duration, i.e. exercise up to 2 X 75 min/day, which did not induce significant changes in body composition, skeletal muscle glycogen levels or citrate synthase activity, resulted in a significant improvement of IV glucose tolerance and substantial reductions of basal and glucose-stimulated plasma insulin levels. Associated with this apparent improvement of insulin sensitivity in vivo, significant increases of the insulin-stimulated glucose uptake (+ 55%) and lactate oxidation + 78%) in vitro were found on perfusion of the isolated hindquarter of swim-trained animals. It is suggested that mild physical training can improve glucose tolerance and insulin sensitivity in normal rats, at least in part, due to an increase of insulin sensitivity of skeletal muscle glucose metabolism.

Effect of hyperthyroidism on insulin and glucose dynamics in rabbits.

Studies with New Zealand rabbits were done to determine the effect of hyperthyroidism on glucose utilization and insulin secretion. Tolerance tests were performed while the animals were euthyroid, and then repeated after the animals had been rendered hyperthyroid by daily sc sodium thyroxine administration (100 μg/kg/day). After the induction of hyperthyroidism, there was an increase in intravenous glucose disposal rate constant (KG) after glucose administration with no alteration in glucose—stimulated plasma insulin levels. Tissue sensitivity to insulin, and insulin half—life, were evaluated by iv injection of 0.15 U insulin per kg body wt. Hyperthyroidism produced an increase in the glucose disposal rate constant (KI) after insulin administration and a significant lowering of the glucose nadir indicating enhanced insulin sensitivity. A decreased insulin half-life was also noted during the hyperthyroid state (3.4 ± 0.3 min) as compared to the control state (5.6 ± 0.3 min). In vitro pancreas incubation st...